L-proline modulated zirconium metal organic frameworks: Simple chiral catalysts for the aldol addition reaction

Article abstract of DOI:10.1016/j.jcat.2018.06.013

Three L-proline modulated zirconium based MOFs denoted as UiO-66, Zr-NDC (NDC = 2,6-Naphthalenedicarboxylate) and UiO-67 were synthesized, characterized and explored as heterogeneous catalyst in diastereoselective aldol addition reactions between 4-nitrobenzaldehyde and linear/cyclic ketones. Upon L-proline modulation, chirality was introduced into these Zr-MOFs which were consequently explored as chiral catalysts for asymmetric reactions. A systematic study was conducted to look into the effect of the synthesis temperature on the modulation in each Zr-MOF. The modulated UiO-66 material synthesized at 120 °C exhibited full conversion and a good diastereoselectivity whereas the homogeneous L-proline catalyst showed only 61% conversion and a reversed diastereoselectivity. The catalyst exhibited no leaching of the catalytically active species and was reused for at least three additional cycles. The observed high catalytic activity is a result of the electron withdrawing nature of the Zr-node coordinated to L-proline.

Full text of DOI:10.1016/j.jcat.2018.06.013

Journal of Catalysis 365 (2018) 36–42
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
L-proline modulated zirconium metal organic frameworks: Simple chiral
catalysts for the aldol addition reaction
⇑
Xiao Feng, Himanshu Sekhar Jena, Karen Leus, Guangbo Wang, Judith Ouwehand, Pascal Van Der Voort
Department of Chemistry, Center for Ordered Materials, Organometallics and Catalysis (COMOC), Ghent University, 281 Krijgslaan (S3), B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Three L-proline modulated zirconium based MOFs denoted as UiO-66, Zr-NDC (NDC = 2,6-Naphthalene
dicarboxylate) and UiO-67 were synthesized, characterized and explored as heterogeneous catalyst in
diastereoselective aldol addition reactions between 4-nitrobenzaldehyde and linear/cyclic ketones.
Received 18 April 2018
Revised 8 June 2018
Accepted 12 June 2018
Upon L-proline modulation, chirality was introduced into these Zr-MOFs which were consequently
explored as chiral catalysts for asymmetric reactions. A systematic study was conducted to look into
the effect of the synthesis temperature on the modulation in each Zr-MOF. The modulated UiO-66 mate-
rial synthesized at 120 °C exhibited full conversion and a good diastereoselectivity whereas the homoge-
neous L-proline catalyst showed only 61% conversion and a reversed diastereoselectivity. The catalyst
exhibited no leaching of the catalytically active species and was reused for at least three additional cycles.
The observed high catalytic activity is a result of the electron withdrawing nature of the Zr-node coordi-
Keywords:
Modulation synthesis
Defect
Zr-MOFs
L-proline
nated to L-proline.
Aldol reaction
Ó 2018 Elsevier Inc. All rights reserved.
1. Introduction
linker. However, functionalization of MOFs by grafting or post syn-
thetic modifications of the linkers demands complex reaction pro-
tocols, expensive multistep synthesis and several instrumental
methods for their characterization.
Asymmetric aldol reactions are very important C-C coupling
reactions in organic chemistry and are catalyzed by proline as a
homogenous catalyst [8,9]. Recently, proline functionalized MOFs
were explored for such applications [10–15]. For example, Kaskel
et al. [10], reported proline functionalized Zr-MOFs (UiO-67 and
UiO-68) by pre-synthetic modification of the organic linker and
achieved good diastereoselectivity after 10 days of reaction. Subse-
In catalysis, both homogeneous and heterogeneous catalysts
have their own advantages and disadvantages. Homogeneous cat-
alysts exhibit high catalytic activity and selectivity but are difficult
to recover and reuse. Heterogeneous catalysts are easy to recover
and reuse but it is difficult to identify the active site that is respon-
sible for the catalytic activity. Researchers are trying to bridge this
gap between homogeneous and heterogeneous catalysis by design-
ing different kinds of supports having active catalytic binding sites
[1,2]. Among them, Metal Organic Frameworks (MOFs) have shown
great potential because they display many properties of an ideal
heterogeneous catalyst such as crystallinity, active-site uniformity,
high surface area, and permanent porosity [3–6]. Therefore, MOFs
are intensively explored for a variety of catalytic applications [6,7],
including hydrogenations, oxidation reactions and asymmetric
catalysis. Generally, three approaches are used to design catalytic
active MOFs, (i) MOFs having unsaturated metal sites, (ii) post-
synthetic modifications of linker/functional organic sites, (iii)
encapsulation of transition metal complexes or metal nanoparti-
cles into the channels/cages [6]. Specifically, for chiral catalysis,
MOFs are integrated with chiral ligands, by either direct grafting
them onto the linker or post-synthetic modification of the achiral
quently, the same group reported another L-proline functionalized
zirconium-MOF [16], denoted as DUT-67 as heterogeneous catalyst
for asymmetric Michael addition reaction in which the parent
monocarboxylic ligand was exchanged with
days of treatment.
L-proline after five
The term ‘‘coordination modulation”, introduced in 2009 by
Kitagawa et al. [17], refers to the use of mono-functional modula-
tors (e.g. monocarboxylic acids) as competitive coordination
agents in the synthesis of MOFs. Importantly, modulators not only
regulate the pore size and morphology of the crystals [18,19], but
also promote the formation of defects [20–23], which in turn
allows the sophisticated tuning of the porosity, stability and cat-
alytic reactivity [24–26]. Nowadays, the modulation synthesis
has become a common approach for defect engineering in MOFs
[20]. Modulated MOFs to create defect sites were used in
⇑
Corresponding author.
E-mail address: Pascal.VanDerVoort@UGent.be (P. Van Der Voort).
https://doi.org/10.1016/j.jcat.2018.06.013
0021-9517/Ó 2018 Elsevier Inc. All rights reserved.

X. Feng et al. / Journal of Catalysis 365 (2018) 36–42
37
heterogeneous Brønsted [27] and Lewis acid [28] catalysis.
Recently, Lillerud et al. introduced a ‘‘functionalized modulator”
– a monocarboxylic acid having other functionalized groups –
and exploited post-synthetic ligand exchange for CO2 adsorption
[29]. Therefore, designing functionalized modulators presents a
new opportunity to create highly active and functionalized low-
cost catalysts with less effort.
changed from 30 to 62% over a period of 7 min. The chirality of
the aldol products was analyzed by chiral HPLC (Chiralpak AS-H;
hexane/ethanol, 90:10). Besides acetone also two other substrates
were examined. For these substrates 4-nitrobenzaldehyde (0.3
mmol) and cyclohexanone (3 mmol) or cyclooctanone (3 mmol)
was placed in a 15 mL screwed glass vial and stirred in 1.5 mL sol-
vent at 45 °C for 24 h. The conversion and diastereoselectivity were
determined using the same non-chiral column under equal condi-
In this work, we synthesized three L-proline functionalized
modulated zirconium MOFs denoted as UiO-66, Zr-NDC and UiO-
67 at three different synthesis temperatures and explored their
catalytic activity in diastereoselective aldol addition reactions. In
tions. Enantioselectivities were measured by chiral HPLC (LUXÒ
5
mm Amylose-1, 250x4.6 mm, hexane/iPrOH, 91:9). After the first
run, the catalyst was removed by filtration, repeatedly washed
with acetone and dried at 150 °C under vacuum before reuse in
the subsequent runs.
these Zr-MOFs, L-proline is not only used as a modulator but is also
employed to introduce the chiral active site. Moreover, a system-
atic study was conducted to examine the influence of the temper-
ature on the number of defects and the density of modulator
present in the framework.
3. Results and discussion
3.1. Effect of temperature on the synthesis of
MOFs
L-proline modulated Zr-
2. Experimental details
2.1. General procedures
Three zirconium based MOFs, UiO-66 [32], Zr-NDC [33] and
UiO-67 [34], were synthesized in the presence of -proline as mod-
ulator. Each MOF was synthesized at three different temperatures
(70 °C, 120 °C and 150 °C) to explore the temperature effect on the
density of defects in the resulting framework (Scheme 1). The
L
All chemicals were purchased from Sigma Aldrich, ABCR, TCI
Europe and used without further purification. X-ray powder
diffraction (XRPD) patterns were collected on an ARL X’TRA X-ray
diffractometer operating at 40 kV/40 mA using Cu-K
a radiation
experimentally obtained ratio of L-proline and linker in each Zr-
MOF was calculated by means of 1H NMR analysis by digesting
the sample in a mixture of D2SO4 and DMSO (Figs. S6–S8). Further-
more, the number of defects was calculated using TGA analysis
(Table 1, Figs. 3, S4 and S5) in accordance to Lillerud’s method
[35]. The powder X-ray diffraction patterns of the obtained
(k = 0.15418 nm) and a solid-state detector. Nitrogen adsorption
experiments were carried out at 77 K using a Belsorp-mini II gas
analyzer. Prior to adsorption measurements, the samples were
activated under vacuum at 150 °C for 16 h to remove the adsorbed
solvent. Thermogravimetric analysis (TGA) was performed on a
Netzsch STA 449 F3 Jupiter in a temperature range of 20–600 °C
in air and a heating rate of 5 °C/min. For 1H NMR, the samples were
dissolved in a heated mixture of D2SO4 and [D6] DMSO (1:6). Spec-
tra were recorded on a Bruker 300 MHz ADVANCE spectrometer.
L-proline modulated Zr-MOFs corresponds well with the non-
modulated Zr-MOFs reported in the literature demonstrating that
the crystalline structure is preserved during the modulation
approach (Figs. 1, S1). The nitrogen adsorption analysis confirmed
that the porosities of these materials depend on the densities of
defects and modulator as can be seen from Figs. 2, S2 and S3).
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.jcat.2018.06.013.
2.2. Synthesis of the catalysts
The proline modulated Zr-MOFs were synthesized following the
procedure of Gutov et al. and Marshall et al. [30,31] Briefly,
ZrO2Cl2Á8H2O (485 mg, 1.51 mmol), the dicarboxylic acid
UiO-66-LP-120 and UiO-66-LP-150 (LP = L-proline) exhibited a
similar Langmuir surface area, whereas the Langmuir surface area
of the UiO-66-LP-70 is slightly higher (Table 1). As shown in
Table 1, UiO-66-LP-120 and UiO-66-LP-150 have an equal amount
(251 mg, 1.51 mmol), HCl (0.625 mL, 7.55 mmol) and L-proline
(866 mg, 7.55 mmol) were dissolved in 20 mL DMF in an ultrasonic
bath for 30 min. The resulting mixture was placed in a Teflon-lined
autoclave at 150 °C, 120 °C or 70 °C for 4 days, and successively
cooled to room temperature. The solid was collected by filtration,
subsequently stirred in DMF at 70 °C for 24 h followed by stirring
in methanol for 24 h to remove unreacted linker, modulator and
DMF. The final purified product was dried under vacuum at 65 °C
before use in catalysis.
of missing BDC linkers and a quasi-similar number of L-proline
modulators whereas UiO-66-LP-70 has a higher number of missing
BDC linkers which results into a higher surface area. Furthermore,
one can see an increase of the ratio of modulator and linker with
decreasing synthesis temperature, whereas a similar trend is
observed for the number of missing linkers.
Similarly, a series of Zr-NDC-LP MOFs were obtained at three
different temperatures. Based on the defect analysis, it was found
that Zr-NDC-LP-70 has the largest number of missing NDC linkers
and highest amount of defects (Table 1). As can be seen from
Table 1, the number of missing linkers and ratio of modulator
and linker increased with decreasing temperature which was also
2.3. General procedure for the catalytic reactions
The catalysts (20 mol% regarding the amount of proline groups
with respect to the 4-nitrobenzaldehyde concentration) were
placed in a 15 mL screwed glass vial under vacuum at 150 °C for
16 h. Afterwards, a mixture of 4-nitrobenzaldehyde (0.03 mmol/
mLÀ1), methyl 4-nitrobenzoate (internal standard, 0.022 mmol/
mLÀ1), acetone (50 vol%) and a solvent (50 vol%) were added and
stirred at 20 or 45 °C for 24 h. The conversion and selectivity was
determined by means of HPLC (Shimadzu LC-20AT) having a C18
column equipped with a SPD-M20A UV detector and LC-Solution
software. The HPLC apparatus was operated at a column tempera-
ture of 30 °C by using a gradient method with water (0.1% trifluo-
roacetic acid) and acetonitrile (HPLC grade) as solvents. In this
gradient method, the volumetric percentage of acetonitrile was
Scheme 1. Synthesis of UiO-66 using L-proline as modulator.

38
X. Feng et al. / Journal of Catalysis 365 (2018) 36–42
Table 1
Structural properties of the three Zr-MOFs and the obtained number of defects at various synthesis temperatures.
150 °C
120 °C
70 °C
Zr-MOFs
SLangmuir (m2gÀ1
)
Mod/La Number of missing SLangmuir (m2gÀ1
linker (per Zr6)b
)
Mod/La Number of missing SLangmuir (m2gÀ1
linker (per Zr6)b
)
Mod/La Number of missing
linker (per Zr6)b
UiO-66-LP 1572
Zr-NDC-LP 1625
UiO-67-LP 1607
0.77
0.51
0.51
2
1.5
0.8
1567
1050
1806
(meso)
0.82
0.67
0.57
2
2.3
1
1850
900
2800
0.85
0.94
0
2.7
3
0
(meso)
a
Defined as Mod/L (mol/mol) by NMR.
Calculated by TGA according to Lillerud’s work [35].
b
UiO-66-LP-70
UiO-66-LP-120
UiO-66-LP-150
Simulated for UiO-66
10
20
30
(°)
40
50
2
Fig. 3. TGA results of the UiO-66-LP synthesized 150 °C, 120 °C and 70 °C
respectively.
Fig. 1. PXRD pattern of the UiO-66-LP materials synthesized at 150 °C, 120 °C and
70 °C respectively.
comparison to the organic linker. This not only results in a reduced
surface area but also in a less crystalline material (Fig. S1).
For the synthesized UiO-67-LP MOFs, structural changes were
noticed along the entire temperature range from low to high
(Table 1). Although, this set of materials was synthesized similarly
to UiO-66-LP and Zr-NDC-LP. UiO-67-LP-70 was found to be micro-
porous in nature whereas UiO-67-LP-120 and UiO-67-LP-150 have
hierarchical pores (Fig. S3). From the PXRD analysis, all three UiO-
67-LPs maintained the original UiO-67 structure and the observed
shoulder peak coming off of the main peak in the case of both UiO-
67-LP-150 and UiO-67-LP-120 suggests structural changes from
microsporous to mesoporous (Fig. S1). The decrease in surface area
at higher temperature is due to the competition of L-proline with
H2BPDC linkers that form mesopores by linking micropores and
replacing the linker. A similar trend is observed in terms of the
ratio of modulator to linker and the number of missing linker,
except the UiO-67-LP-70. From the 1H NMR and TGA analysis
(Table 1; Figs. S5, S8), it was found that, in contrast to the UiO-
66-LP and the Zr-NDC-LP MOFs, UiO-67-LP-70 has no defects pre-
sent in the structure. A similar observation was noted in the
reported modulated UiO-67 MOF [30]. From both observations
one can conclude that 70 °C is the best temperature to obtain an
ideal crystalline UiO-67 MOF structure probably because the linker
has low solubility at the temperature.
Based on these observations, one can conclude that the use of
modulators at low synthesis temperatures have competitive
advantages in comparison to the organic linker. So in general, more
defects and relative high densities of modulators were obtained at
low synthesis temperature.
Fig. 2. Nitrogen adsorption isotherms of the UiO-66-LP materials synthesized at
150 °C, 120 °C and 70 °C respectively.
observed for the UiO-66-LP materials. In contrast to the UiO-66-LP
and UiO-67-LP materials which showed an increase in surface area
when the synthesis temperature was decreased, the Zr-NDC-LP
materials show the opposite (Fig. S2). More specifically, here a
decrease in surface area was noted when the synthesis tempera-
ture was lowered. This is probably due to the fact that the
modulator is preferentially introduced into the framework in

X. Feng et al. / Journal of Catalysis 365 (2018) 36–42
39
3.2. Evaluation of the modulated Zr-MOFs as catalysts in the aldol
reaction
quite low. Complete conversion was obtained in pure acetone after
24 h with a selectivity of 89%. A few drops of water inhibited the
formation of the dehydration product with a selectivity of 99%
for 1 but the conversion itself was decreased to 89%. This is because
acetone can facilitate the transport of substrates and products in
the framework more efficiently and stabilizes the reaction inter-
mediates via H-bonding interaction.
In general, defects in Zr-MOFs appear either when linkers or Zr
clusters or both are missing in the framework. This causes an open
coordination site around each Secondary Building Unit (SBU).
These open sites can be occupied by the modulator or by decom-
posed products of the solvent used in the reactions (basically
decomposed DMF). However, due to charge compensation and its
coordination ability, the modulator has a higher coordination prob-
ability than the others. At a low temperature, the modulator is
more likely to coordinate on the zirconium metal node and has a
better chance to behave as Brønsted and Lewis acid catalysts. Sev-
eral studies already demonstrated that a modulator is a compen-
sating/capping ligand coordinated to the metal node which was
confirmed through ion exchange [30,36]. Based on this knowledge,
After screening the aldol reaction with L-proline modulated Zr-
MOFs, it was confirmed that UiO-66-LP-120 and UiO-66-LP-150
have the best catalytic activity. Therefore, the reaction protocol
using UiO-66-LP-120 was extended to asymmetric aldol reactions
using 4-nitrobenzaldehyde and cyclohexanone as substrate. Theo-
retically, four different aldol products including two syn and two
anti can be expected from this reaction. Therefore, two pairs of
diastereoisomers: syn and anti-products were analyzed by HPLC
analysis. During the solvent screening, it was found that DCM
offered the best substrate conversion whereas methanol gave the
highest diastereoselectivity (desyn = 64) (Table 3). Notably, the
obtained diastereoselectivity is opposite to that observed using
we introduced L-proline to create an active chiral site for asymmet-
ric aldol reactions.
The catalytic activity of L-proline modulated Zr-MOFs were
explored in the aldol reaction between 4-nitrobenzaldehyde and
acetone at room temperature. Table 2 shows the catalytic perfor-
the homogenous L-proline as catalyst [8].
The use of a polar solvent is the best medium to achieve optimum
reactivity because it facilitates substrate/product transport and sta-
bilizes the enamine intermediates by H-bonding interaction.
Penhoat et al. studied the strong influence of Lewis acid with
mance of the
expected, two aldol products, the b-hydroxy carbonyl compound
(1) and , b-unsaturated carbonyl compound (2) were obtained.
L-proline modulated Zr-MOFs in this reaction. As
a
Amongst the several modulated Zr-MOFs, the UiO-66-LP materials
exhibit the best catalytic activity (Table 2). The UiO-66-LP-70 has
the highest number of defects but has the lowest reactivity. UiO-
66-LP-120 and UiO-66-LP-150 have a similar reactivity with high
conversion and selectivity for 1. To verify the reason for this differ-
ence in catalytic reactivity, all the catalysts were characterized by
means of PXRD and nitrogen adsorption after the catalytic reaction.
As can be seen from Fig. S9 the UiO-66-LP-150 and UiO-66-LP-120
material remained intact after this reaction. However, the UiO-66-
LP-70 lost its structure and surface area. This is probably due to the
fact that the latter material has the largest amount of defects and
missing linkers [28,35,37]. Also the Zr-NDC and UiO-67 showed lit-
tle stability during the catalysis which might be due to the defects
present in the structure (Figs. S10–S12) [38]. The UiO-67-LP-70
L-proline in an aldol reaction and envisaged the formation of a cat-
alytic active complex based on Zn2+ coordinated with proline [39].
We assume that the good catalytic performance of the modulated
Zr-MOF materials presented in this study can be assigned to the
beneficial formation of the L-proline intermediate state which is pro-
duced due to the electron withdrawing nature of the Zr node (Fig. 4).
Furthermore, to explore the influence of the pore confinement,
cyclooctanone was used as substrate. This substrate was chosen
because it has a larger kinetic diameter than the pore size of UiO-
66. The catalytic activity of UiO-66-LP-120 using cyclooctanone as
substrate was low in comparison to that of using cyclohexanone as
substrate (Table S4). Only 18% of conversion was obtained when
using cyclooctanone as a substrate. This activity could be assigned
to the active sites that are located on the outer surface of the catalyst.
Additionally, the catalyst’s reusability was explored by recover-
ing the catalyst from the reaction mixture and reusing it in three
additional cycles (Figs. 5b, S13). During these successive cycles, a
slight decrease in the conversion was noticed while the diastereos-
electivity remained the same. From the PXRD measurements of
that is stable and does not contain
showed a very low conversion.
L-proline in its structure also
Upon changing the solvent, it was found that in acetone the
UiO-66-LP-120 shows the highest conversion (Table S2). Although
a better selectivity is observed in pure water, the conversion is
Table 2
Catalytic studies for the aldol addition of 4-nitrobenzaldehyde and acetone using Zr based MOF catalysts.
Catalyst
-proline
T(°C)
t(h)
24
Conversion (%)
99
Selectivitya (%)
87
20
L
UiO-66-LP-150
UiO-66-LP-120
UiO-66-LP-70
Zr-NDC-LP-150
Zr-NDC-LP-120
Zr-NDC-LP-70
UiO-67-LP-150
UiO-67-LP-120
UiO-67-LP-70
20
20
20
20
20
20
20
20
20
24
24
24
24
24
24
24
24
24
60
62
4
8
3
2
6
3
3
96
96
75
89
70
70
83
85
79
Reaction conditions: 20 °C, 0.3 mmol of 4-nitrobenzaldehyde, 10 mL acetone, 20 mol % catalyst (related to the proline amount in the material).
a
Towards aldol product 1.

40
X. Feng et al. / Journal of Catalysis 365 (2018) 36–42
Table 3
Solvent screening for diastereoselective aldol Reaction.
a
Solvent
-proline DMSO
t(h)
Conversion (%)
dr (syn:anti)
desyn(%)
TOF (S-1
0.0013
)
24
(72)
24
24
24
24
24
53
(61)
70
94
100
22
50:50
(42:58)
60:40
66:34
68:32
77:23
82:18
0
L
(À1 6)
Hexane
chloroform
DCM
DMSO
Methanol
20
–
–
32
36
54
64
0.00056
–
0.00046
95
Reaction conditions: 45 °C, 0.3 mmol of 4-nitrobenzaldehyde, 3 mmol cyclohexanone, 1.5 mL solvent, 20 mol % catalyst (related to the proline amount in the material).
a
TOF calculated at 30 min.
Fig. 4. Proposed mechanism of aldol reaction using UiO-66-LP-120.
the recovered catalyst, it was confirmed that UiO-66-LP-120
retained its structural framework even after three reaction
cycles (Figs. S14, S15). This ruled out the possibility of the frame-
work’s decomposition. Nitrogen adsorption analysis of the recov-
ered catalyst showed only a marginal decrease in the porosity
suggesting a slight pore blocking or blocking of the catalytic site
(Figs. S14, S15).
To further verify the leaching of proline, a hot filtration test was
performed after 3 h of reaction. As shown in Fig. 5a, the catalytic
reaction did not proceed even after 48 h. This ruled out the leach-
ing of proline species during the catalysis. This result further sup-
ports that the decrease in catalytic activity during the additional
runs might be due to pore blocking or blocking of the active site
around the SBU.
In addition, a comparison was made between our proline mod-
ulated Zr-MOFs and the ones reported in literature (see Table S5).
Although it is hard to give a fair comparison because different reac-
tion conditions were used, one can see from this table that the
modulated Zr-MOFs presented in this study displayed the highest
catalytic activity in comparison to the reported proline functional-
ized MOFs at present [10–15]. The UiO-66-LP-120 material used in
this study exhibited approximately full conversion after 24 h of
reaction time for the substrate cyclohexanone whereas the best
performing catalyst reported in literature, denoted as UiO-68-
NHPro, exhibited full conversion after 10 days of reaction having
a similar diastereoselectivity as our best performing catalyst. Fur-
thermore in comparison to the homogeneous counterpart which
only exhibited
a conversion of 61% using cyclohexanone as

X. Feng et al. / Journal of Catalysis 365 (2018) 36–42
41
grateful to the Flemish government (VLAIO) for providing funding
through grant number 150663.
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Acknowledgement
X. Feng and G. Wang gratefully acknowledge the Chinese Schol-
arship Council (CSC) and Ghent University BOF Co-funding grant
for financial support. K. Leus acknowledges the financial support
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Sklodowska-Curie grant agreement No 665501. J. Ouwehand is

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